Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-10-06
2001-04-10
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S509000
Reexamination Certificate
active
06214823
ABSTRACT:
BACKGROUND OF THE INVENTION
Arrhythmias often occur as complications to cardiac diseases such as myocardial infarction and heart failure. In serious cases, arrhythmias may give rise to ventricular fibrillation which can cause sudden death.
According to the classification of Vaughan-Williams, there are four distinct classes of antiarrhythmic agents. Class I antiarrhythmic agents are those agents which provide for sodium channel blockade, including those compounds which exert a membrane stabilizing effect. Exemplary of this class of compounds are quinidine, procainamide, disopyramide, lidocane, tocainide, flecainide and propafenone. Class II antiarrhythmic compounds are agents which block sympathetic activity. Exemplary of this class of compounds are propranolol and acebutolol. Class III antiarrhythmic agents are compounds which prolong the effective refractory period without altering the resting membrane potential or rate of depolarization. Compounds such as amiodarone, bretylium and sotalol are considered to be in this class. Class IV antiarrhythmic agents are effective in calcium channel blockade. Exemplary of this class of compounds are diltiazem and verapamil. Further definition of these classes can be found in Pharma Projects, section C1B, May 1993.
Though various antiarrythmic agents are now available on the market, agents which exhibit both satisfactory effects and high safety profiles have not been marketed, For example, antiarrythmic agents of Class I, which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax), are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety as they cause a depression of the myocardial contractility and have a tendency to induce arrythmias due to an inhibition of the impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrythmic agents of Class III are drugs which cause a selective prolongation of the duration of the action potential without a significant depression of the Vmax. Drugs in this class are limited. Drugs such as sotalol and amiodarone have been shown to possess Class III properties. Sotalol also possesses Class II effects which can cause cardiac depression and is therefore contraindicated in certain susceptible patients. Amiodarone is also severely limited by side effects. Drugs of this class are expected to be effective in preventing ventricular fibrillations. Pure Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to the inhibition of the action potential conduction as seen with Class I antiarrhythmic agents.
U.S. Pat. No. 5,658,901 discloses novel 2-oxo-1,4-benzodiazepines which are potent Class III agents. Compounds in this patent, while extremely potent, display extended half lives in animals, resulting in a high potential for toxicity. The compounds of the present invention show a decreased half-life in animals.
U.S. Pat. Nos. 5,595,900 and 5,631,251 disclose additional antiarrhythmic benzodiazepines.
SUMMARY OF THE INVENTION
This invention relates to compounds of the general formula
wherein
R
1
is
1) phenyl,
2) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl,
e) —C
1-3
alkoxy, or
3) cyclopropyl;
R
2
is
1) phenyl,
2) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl,
e) —C
1-3
alkoxy, and
n is 0, 1 or 2;
or a pharmaceutically acceptable addition salt and/or hydrate thereof, or crystal form thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
The invention also relates to pharmaceutical compositions containing said compounds for use in mammals and methods of treating arrhythmia by the administration of one or a combination of the novel compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to compounds of the general formula
wherein
R
1
is
1) phenyl,
2) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl,
e) —C
1-3
alkoxy, or
3) cyclopropyl;
R
2
is
1) phenyl,
2) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl,
e) —C
1-3
alkoxy, and
n is 0, 1 or 2;
or a pharmaceutically acceptable addition salt and/or hydrate thereof, or crystal form thereof, or where applicable, a geometric or optical isomer or racemic mixture thereof.
The compounds of the present invention may have asymmetric centers and occur as racemates, mixtures of enantiomers, individual diastereomers, or as individual enantiomers with all isomeric forms being included in the present invention.
A preferred embodiment of this invention is represented by
wherein
R
2
is
1) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl, and
n is 0, 1 or 2.
A second preferred embodiment of this invention is represented by
wherein
R
2
is
1) substituted phenyl, with one or two substituents, selected from the group consisting of
a) -hydrogen,
b) —Cl, Br, F, or I,
c) —CF
3
,
d) —C
1-3
alkyl, and
n is 0, 1 or 2.
Unless otherwise stated or indicated, the following definitions shall apply throughout the specification and claims.
When any variable occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, e.g., methyl (Me), ethyl (Et), propyl, butyl, pentyl, hexyl, heptyl, octyl, nonanyl, decyl, undecyl, dodecyl, and the isomers thereof such as isopropyl (i-Pr), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), isopentane, isohexane, etc.
The term “halogen” or “halo” is intended to include fluorine, chlorine, bromine and iodine.
As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
The optical isomeric forms, that is mixtures of enantiomers, e.g., racemates, or diastereomers as well as individual enantiomers or diastereomers of the instant compound are included. These individual enantiomers are commonly designated according to the optical rotation they effect by the symbols (+) and (−), (L) and (D), (1) and (d) or combinations thereof. These isomers may also be designated according to their absolute spatial configuration by (S) and (R), which stands for sinister and rectus, respectively.
The individual optical isomers may be prepared using conventional resolution procedures, e.g., treatment with an appropriate optically active acid, separating the diastereomers and then recovering the desired isomer. In addition, the individual optical isomers may be prepared by asymmetric synthesis.
Additionally, a given chemical formula or name shall encompass pharmaceutically acceptable addition salts thereof and solvates thereof, such as hydrates.
The compounds of the present invention, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable addition salts for purpo
Butcher John W.
Claremon David A.
Liverton Nigel J.
Selnick Harold G.
Camara Valerie J.
Daniel Mark R.
Jang Soonhee
Merck & Co. , Inc.
Raymond Richard L.
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